Aryl H-Phosphonates 18. Synthesis, properties, and biological activity of 2′,3′-dideoxynucleoside (N-heteroaryl)phosphoramidates of increased lipophilicity (original) (raw)
The Journal of Organic Chemistry, 1997
Various approaches to the synthesis of nucleoside H-phosphonamidates have been investigated. Direct couplings of nucleoside H-phosphonates with amines have been hampered by extensive reactions of the condensing agents with amines. Preactivation of nucleoside H-phosphonates with pivaloyl chloride or chlorophosphates, followed by the addition of amines, notably diminished these side reactions. The most efficient and versatile route to nucleoside N-alkyl H-phosphonates was found to be aminolysis of the in situ-produced aryl nucleoside H-phosphonates with appropriate amines.
Bioorganic & Medicinal Chemistry, 2006
Aryl nucleoside 5 0 -H-phosphonates 4 bearing AZT or 2 0 ,3 0 -dideoxyuridine moieties were subjected to reaction with various aromatic aldehydes to produce nucleoside 5 0 -a-hydroxyphosphonate derivatives 2 as potential anti-HIV agents. Stability of the title compounds in cell culture media was investigated and three distinct decomposition pathways were identified. The anti-HIV activity of hydroxyphosphonates 2 correlates well with the type and extent of their chemical or enzymatic degradation in culture medium (RPMI 1640 containing 10% FBS), suggesting that aryl nucleoside 5 0 -hydroxyphosphonates 2 act as depot forms of the parent antiviral nucleosides. 0.1 M PB, pH 7.4 or RPMI/FBS AZT = 3'-deoxy-3'-azidothymidin-5'-yl Ph = phenyl Ar = 4-methoxyphenyl PB = 0.1 M phosphate buffer pH 7.4 FBS = fetal bovine serum RPMI = RPMI 1640 Scheme 1. Decomposition of 1 in PB, pH 7.4, and RPMI/FBS 10% (v/v) 37°C.
Phosphorylation of nucleoside derivatives with aryl phosphoramidochloridates
Tetrahedron, 1975
AM-The preparation of three aryl phosphorocyclohexylamidochloridates (7a, 7b and 7c) and an aryl phosphoromorpholidochoridate (8) is described. These aryl phosphoramidochloridates react with 2',3'-Omethoxymethylene-uridine,-4-N-anisoylcytidine and AN-anisoyladenosine (9a, 9b and 9e, respectively), in the presence of the l-ethylimidazole derivative (lla) to give high yields of the corresponding fully-protected 5'-phosphoramidates (IO). Treatment of the latter compounds with aqueous alkali gives the nucleoside 5'-phosphoramidate derivatives (14) which, on mild acidic hydrolysis, give the corresponding unprotected 5'-nucleotides (15) in virtually quantitative yields. Phosphorylation of 2'-0-methoxytetrahydpyranyhuidine (12) with 7a and 8, under the same conditions, occurs regiospecifically to give the corresponding S'-phosphoramidate derivatives (13). The partially-protected dinucleoside phosphate (164~) has been prepared and phosphorylated with 7a to give, after removal of the protecting groups, the dinucleotide (18, pUpU) in high yield.
Bioorganic & Medicinal Chemistry, 2009
Di-aryl nucleoside phosphotriesters have been explored as a new type of pronucleotides for the purpose of anti-HIV-1 therapy and efficient synthetic protocols, based on H-phosphonate chemistry, have been developed for the preparation of this class of compounds. It was found that anti-HIV-1 activity of the phosphotriesters bearing an antiviral nucleoside moiety (AZT, ddA) and also ddU was due, at least partially, to intracellular conversion into the corresponding nucleoside 5 0 -monophosphates, and their efficiency correlated well with the pK a values of the aryloxy groups present. j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b m c 4.1.5.10. 3 0 -Azido-3'-deoxythymidyn-5 0 -yl 2-chloropyridin-3-yl phosphate triethylammonium salt (4aj). Yield 0.14 g (71%). 1 H NMR (CDCl 3 ) d 11.87 (br s, 1H, exch. D 2 O), 9.00 (br s, 1H, exch. D 2 O), 8.07 (dd, J = 4.8 Hz, J = 1.5 Hz, 1H), 7.97 (dd, J = 8.4 Hz, J = 1.5 Hz, 1H), 7.66 (q, J = 0.9 Hz, 1H), 7.16 (dd, J = 8.4 Hz, J = 4.8 Hz, 1H), 6.26 (t, J = 6.6 Hz, 1H), 4.46-4.37 (m, 1H), 4.28-4.17 (m, 2H), 4.04-4.01 (m, 1H), 3.06 (q, J = 7.2 Hz, 6H), 2.40-2.25 (m, 2H), 1.89 (d, J = 0.9 Hz, 3H), 1.32 (t, J = 7.2 Hz, 9H); 31 P NMR (CDCl 3 ) d À5.99 (t, 3 J HP = 6.4 Hz); HRMS [MÀEt 3 NH + ] À : 457.0450, calcd for C 15 H 15 N 6 O 7 PCl: 457.0429. 4.1.5.11. 3 0 -Azido-3 0 -deoxythymidyn-5'-yl 5-chloropyridin-3-yl phosphate triethylammonium salt (4ak). Yield 0.15 g (79%). 1 H NMR (CDCl 3 ) d 11.86 (br s, 1H, exch. D 2 O), 8.82 (br s, 1H, exch. D 2 O), 8.45 (d, J = 1.5 Hz, 1H), 8.26 (d, J = 1.8 Hz, 1H), 7.71 (dd, J = 1.8 Hz, J = 1.5 Hz, 1H), 7.62 (q, J = 0.9 Hz, 1H), 6.26 (t, J = 6.3 Hz, 1H), 4.40-4.34 (m, 1H), 4.28-4.14 (m, 2H), 4.01 (br m, 1H), 3.06 (q, J = 7.2 Hz, 6H), 2.42-2.25 (m, 2H), 1.88 (d, J = 0.9 Hz, 3H), 1.34 (t, J = 7.2 Hz, 9H). 31 P NMR (CDCl 3 ) d -5.63 (t, 3 J HP = 6.4 Hz); HRMS [MÀEt 3 NH + ] À : 457.0420, calcd for C 15 H 15 N 6 O 7 PCl: 457.0429. 4.1.5.12. 2 0 ,3 0 -Dideoxyuridin-5'-yl phenyl phosphate triethylammonium salt (4ba). Yield 0.07 g (76%). 1 H NMR (CDCl 3 ) d 11.94 (br s, 1H, exch. D 2 O), 9.83 (br s, 1H, exch. D 2 O), 7.84 (d, J = 8.1 Hz, 1H), 7.22-7.15 (m, 4H), 6.98-6.93 (m, 1H), 6.00-5.96 (m, 1H), 5.51 (d, J = 8.1 Hz, 1H), 4.24-4.18 (m, 2H), 4.07-4.00 (m, 1H), 2.97 (q, J = 7.2 Hz, 6H), 2.29-2.22 (m, 1H), 1.97-1.87 (m, 3H), 1.24 (t,, J = 7.2 Hz, 9H). 31 P NMR (CDCl 3 ) d À5.83 (t, 3 J HP = 5.5 Hz); HRMS [MÀEt 3 NH + ] À : 367.0682, calcd for C 15 H 16 N 2 O 7 P: 367.0700. 4.1.5.13. 2 0 ,3 0 -Dideoxyuridin-5 0 -yl pyridin-3-yl phosphate triethylammonium salt (4bb). Yield 0.07 g (72%). 1 H NMR (CDCl 3 ) d 11.73 (br s, 1H, exch. D 2 O), 10.16 (br s, 1H, exch. D 2 O), 8.45 (br s, 1H), 8.2 (d, J = 4.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.17 (dd, J = 8.8 and 4.4 Hz, 1H), 5.97-5.95 (m, 1H), 5.53 (d, J = 8.4 Hz, 1H), 4.21-4.17 (m, 2H), 4.05-4.00 (m, 1H), 2.99 (q, J = 7.2 Hz, 6H), 2.29-2.24 (m, 1H), 1.97-1.87 (m, 3H), 1.24 (t, J = 7.2 Hz, 9H). 31 P NMR (CDCl 3 ) d À5.88 (t, 3 J HP = 5.5 Hz); HRMS [MÀEt 3 NH + ] À : 368.0642, calcd for C 14 H 15 N 3 O 7 P: 368.0648.
Organic Letters, 2009
Chloromethyl polystyrene resin was reacted with 5-hydroxysalicylaldehyde in the presence of potassium carbonate to afford polymer-bound 2-hydroxybenzaldehyde. Subsequent reduction with borane solution produced polymer-bound 2-hydroxybenzyl alcohol. The reaction of immobilized 2hydroxybenzyl alcohol with appropriate phosphitylating reagents yielded solid-phase cycloSaligenyl mono-, di-, and triphosphitylating reagents, which were reacted with unprotected nucleosides, followed by iodine oxidation, deprotection of cyanoethoxy groups, and the basic cleavage, respectively, to afford 5′-O-nucleoside mono-, di-, and triphosphoramidates in 52-73% overall yield. Antiviral and antitumor nucleoside analogs undergo three phosphorylation steps by cellular kinases to generate nucleoside 5′-triphosphates that act as competitive inhibitors of DNA polymerases or incorporate into DNA and cause chain termination. 1 The first phosphorylation step is often the rate-limiting step. Thus several nucleoside phosphoramidate derivatives have
Oligonucleotide N3′→P5′ phosphoramidates as potential therapeutic agents
Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression, 1999
Uniformly modified nucleic acids analogues, oligonucleotide N3PCP5P phosphoramidates, containing 3P-amino instead of 3P-hydroxyl nucleosides, were synthesized and studied. These compounds form very stable duplexes with complementary native phosphodiester DNA and exceptionally stable duplexes with RNA strands. Increases in duplex melting temperature, vT m , relatively to their phosphodiester counterparts, reaches 2.9^3.5³C per modified nucleoside. Moreover, the phosphoramidate compounds form extremely stable triple stranded complexes with single or double stranded DNA oligomers under near physiological salt and pH conditions. Melting temperatures of these triplexes usually exceed that of the isosequential phosphodiester counterparts by up to 35³C. For 11-15-mers 2P-deoxyphosphoramidates are structurally and functionally similar to the native RNA molecules and thus can be used as RNA decoys. They are resistant to enzymatic digestion by nucleases both in vitro and in vivo. Oligonucleotide phosphoramidates apparently are cell permeable, and they have a good bioavailability and biodistribution, while being non-toxic in mice at therapeutically relevant doses. Duplexes of the several studied phosphoramidates with complementary RNA strands apparently are not substrates for RNase H in vitro. Despite that, these compounds exerted high sequence-specific antisense activity in various cell lines and in SCID mice. The observed in vitro lack of RNase H recognition of the RNA:phosphoramidate duplexes may result in better specificity in biological activity of these compounds relative to RNase H inducing oligonucleotides. Experimental results also indicate that oligonucleotide phosphoramidates can be used as efficient and specific modulators of gene expression by an antigene mechanism of action. Finally, the oligo-2P-deoxyphosphoramidate double stranded complexes can structurally mimic native RNA complexes, which could be efficiently and specifically recognized by the RNA binding proteins, such as HIV-1 Rev and Tat. ß
Synthesis and Evaluation of Biological Activity of New Arylphosphoramidates
BioMed Research International, 2018
The synthesis of new substituted arylphosphoramidates is performed in two steps through phosphorylation of the corresponding alcohols followed by aminolysis. The formation of the desired phosphoramidates depends on the subsequent addition of the two alcohols with the amine being added at the last step. The products were obtained in 58–95% yields. They were characterized mainly by multinuclear (1H, 13C, 31P, and 19F) NMR and IR spectroscopy. In addition, the antimicrobial and antiacetylcholinesterase activities were evaluated. The results showed acetylcholinesterase activity by some compounds, whilst no significant inhibitory effect against the tested bacterial strains has been recorded.